These investigations are concerned with the processes and control of lymphoid differentiation, beginning with multipotential stem cells and ending with the mature T and B lymphocytes which mediate immune defense. An important part of these studies is to compare and contrast normal differentiation with the defects which occur in malignancy and in immunodeficiency diseases. Using organ and cell culture techniques we will attempt to define discrete steps in B-cell differentiation from stem cells to mature lymphocytes. These studies will depend on the use of markers to identify stages of B cell differentiation, including pre-B cells and immature B cells, and on correlation of markers with functional activity. Immunoglobulin biosynthesis and secretion will be examined in malignant pre-B cells, hopefully in normal human pre-B cells and in their cellular counterparts in the chicken. Idiotype antibodies will be used to study at a cellular level the generation of clonal diversity in mice and humans. We will also continue to examine in vitro the regulatory interactions between T cells, B cells and macrophages, and those involved in generation of isotype diversity. Attempts will be made to prepare purified antibodies against immunochemically purified T and B cell antigens, and to begin functional analysis of human subpopulations of cells bearing these antigens.